DESCRIPTION (Investigator's Abstract): Our long term goals are to (1) develop an effective therapeutic vaccine to reduce ocular HSV recurrences and (2) ensure that vaccines proposed for human use against HSV-2 genital infections do not unknowingly increase ocular HSV disease. In the United States, approximately 400,000 people per year suffer recurrent ocular herpes simplex virus (HSV) episodes requiring doctor visits and medication. Unfortunately, commercial HSV vaccine development is directed at genital HSV-2. There are little or no efforts to combat ocular HSV (90% of which is HSV-1). The development of a therapeutic vaccine, that is, a vaccine to reduce HSV ocular recurrences, would greatly alleviate what is now the most frequent serious viral eye infection in the U.S. and a major cause of viral induced blindness. The host immune response to natural HSV infection is incomplete or inadequate to control recurrent disease. Development of a therapeutic HSV vaccine is based on the premise that the immune response might be augmented by vaccination with HSV specific immunogens, thereby controlling recurrences. Recent results in animals suggest that specific immune augmentation can result in better control of recurrent HSV infections.However, the ineffectiveness of vaccines used alone or with alum, suggests that to be effective the immunogen must be administered with potent adjuvants. With the advent of genetic engineering to produce new subunit vaccines and the co-development of new synthetic adjuvants it is very likely that virus-specific immunotherapy of recurrent HSV ocular infections can be successfully developed. Our specific are: 1. Development of a therapeutic vaccine that decreases spontaneous HSV-1 ocular shedding and corneal disease in the rabbit ocular model of HSV-1 latency and recurrences. Studied will focus on local ocular vaccination with expressed HSV-1 glycoproteins. Although the immune response to natural HSV infection does not protect against subsequent recurrences, "higher than normal" immune responses obtained using expressed glycoprotein subunit vaccines and an appropriate adjuvant reduced genital HSV-3 recurrences in guinea pigs (page 17). A "higher than normal" immune response was recently obtained in humans with a similar Gd subunit vaccine that increased HSV-2 antibody titers in seropositive individuals 20 fold over that produced by their natural infection (1809). Since we have found that local ocular vaccination protects rabbits against corneal disease following subsequent ocular challenge much better that does systemic vaccination (page 20), ocular inoculation using subunit vaccines should be an effective approach to developing a therapeutic vaccine against ocular HSV recurrences. 2. Ocular safety screening of candidate vaccines for human use in the rabbit ocular model of HSV-1 latency and recurrence. Ocular safety means no increase in spontaneous ocular HSV shedding or corneal disease. We have 5 of the candidate HSV-2 vaccines likely to be used in man. Safety trials will be done using vaccination regimens as close as possible to those proposed for use in man by the developer of the specific candidate vaccine.